It is known that microbial metabolite radicicol represented by the following formula (B) has an antifungal effect and an anticancer effect [Nature, 171, 344 (1953); Neoplasma, 24, 21 (1977)], an immunosuppression effect (Japanese Published Unexamined Patent Application No. 298764/94), or morphology normalization effect of ras or mos canceration cells [Oncogene, 11, 161 (1995)]. ##STR2##
Furthermore, it is known that radicicol derivatives in which the phenolic hydroxyl group is modified with various acyl groups have an antitumor effect (Japanese Published Unexamined Patent Application No. 226991/92). In addition, it is disclosed that radicicol derivatives in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group show an angiogenesis inhibition effect (Japanese Published Unexamined Patent Application No. 279279/94) or an interleukin 1 production inhibition effect (Japanese Published Unexamined Patent Application No. 40893/96). Recently, oxime derivatives of dienone of a radicicol derivative showing antitumor action and immunosuppression action have been published (WO 96/33989: published on Oct. 31, 1996), and antitumor radicicol derivatives represented by the following formula (B') have also been published (Japanese Published Unexamined Patent Application 202781/97: published on Aug. 5, 1997). ##STR3##
(In the formula, R.sup.1p and R.sup.2p represent a hydrogen atom or an acyl group; and X.sup.p represents a halogen atom, a hydroxyl group or a lower alkoxy group.)
Additionally, it is known that ansamycins antibiotics, geldanamycin, represented by formula (C) [The Journal of Antibiotics, 23, 442 (1970)] has tyrosine kinase inhibition activity and antitumor effects [for example, Cancer Research, 52, 1721 (1992) and Cancer Research, 54, 2724 (1994)]. It is shown that these effects are expressed by the inhibition of the activation of a tyrosine kinase, such as Src, ErbB-2, Lck or the like, and a serine/threonine kinase Raf-1, through the formation of a complex of geldanamycin with a molecular chaperone Hsp (heat shock/stress protein) 90 by binding to Hsp90 [for example, Proceedings of the National Academy of Sciences of the, U.S.A, 91, 8324 (1994) and The Journal of Biological Chemistry, 270, 24585 (1995)]. Consequently, drugs capable of acting upon Hsp90 are also included in tyrosine kinase inhibitors and useful not only as antitumor agents but also for the prevention and treatment of various diseases such as osteoporosis, immune diseases, and the like. ##STR4##
Tyrosine kinase is an enzyme which uses ATP as a phosphate donor and catalyzes transfer of its .gamma.-phosphate group to the hydroxyl group of a specified tyrosine residue of a substrate protein, thereby taking an important role in the control mechanism of intracellular signal transduction. Various tyrosine kinase families are known. Tyrosine kinase activities, such as Src in colon cancer, ErbB-2 in breast cancer and gastric cancer, Ab1 in leukemia, and the like, increase. Disordered increase in the tyrosine kinase activity causes abnormal differentiation and proliferation of cells. Consequently, specific inhibitors of tyrosine kinase are useful in preventing and treating various diseases, including as antitumor agents.
Lck is a tyrosine kinase which is activated when T lymphocytes are activated by antigen stimulation, and an inhibitor of this enzyme is useful as an immunosuppressant. Also, it is known that Src relates to bone resorption in osteoclast, and an inhibitor of this tyrosine kinase is useful as a bone resorption inhibitor for the treatment of osteoporosis. Additionally, inhibitors of receptor type tyrosine kinases of various growth factors, such as EGF-R (epidermal growth factor receptor), FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor), and the like, are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor, and the like.